Healthy smokers (without COPD) have increased occurrence of airway infections compared to non-smokers,[unreadable] and smoking is also the major risk factor for COPD. COPD is characterized by chronic airway obstruction,[unreadable] decreased mucociliary clearance (MCC), mucus hypersecretion, and chronic airway inflammation. Bacterial[unreadable] and viral infections are the leading causes of acute exacerbations of COPD. . In Cystic Fibrosis (CF),[unreadable] dehydration of the airway surface liquid (ASL) leads to decreased mucociliary clearance (MCC), colonization[unreadable] by bacteria and frequent exacerbations of disease related to MCC failure. The CFTR-induced anomalies in[unreadable] ASL solute concentration and subsequent ASL dehydration are a central cause of CF lung disease. Clinical[unreadable] similarities between COPD and Cystic Fibrosis (CF) suggest that despite differences in pathogenesis, there[unreadable] are key similarities in their pathophysiology. Adenosine and purinergic control of airway hydration are likely[unreadable] important in both diseases, as we have observed that (like CF) COPD patients also have decreased ASL[unreadable] dehydration and adenosine levels relative to normal volunteers. The overarching hypothesis of this project is[unreadable] that smoking predisposes to decreased MCC due to ASL dehydration, partly due to decreased ASL[unreadable] adenosine and diminished innate host defense. In Project IV, we will test the hypothesis that smokers have[unreadable] decreased MCC with alterations in purine and adenosine biology by comparing these airway processes[unreadable] between normal volunteers and smokers. We also hypothesize that smoking will cause decreased[unreadable] macrophage function and bacterial colonization of the airway. We will compare our results in normal[unreadable] volunteers and smokers to those from similarly studied COPD (Project V) and CF (Project VI) patients, as we[unreadable] suspect that smoking-induced changes will mimic those in COPD. We will also examine MCC, hydration and[unreadable] airway responses in normal volunteers and smokers after challenge with inhaled endotoxin (a bacterial[unreadable] product found in tobacco smoke) and experimental viral infection to determine if MCC in smokers is less[unreadable] adaptive to these challenges. These aims will provide novel in vivo data on smoking-induced airway[unreadable] pathophysiology in humans. The medical significance of these studies is that they will firmly establish the[unreadable] importance of mucus clearance to maintain respiratory health and will elucidate disease mechanisms and[unreadable] therapeutic targets applicable for many chronic obstructive airway diseases.